Abdominal aortic aneurysms (AAAs) are an important vascular condition in the United States and other developed nations, where a progressive increase in incidence has been observed over the past 30 years (Mitchell et al., Vascular Surgery, 4th edition, 1995, 1032-1060). The majority of AAAs affect men over the age of 55, but a steady rise in incidence has also been observed in women (Cole et al., Chronic Dis. Canada, 1994, 15:S1-S64; Krupski et al. Semin. Vasc. Surg., 1995, 8:83-167).
Elastin and collagen (types I and III) are the principal structural proteins of the aorta. These fibrillar proteins impart both strength and resilience to the aortic wall during its continual exposure to the stress of pulsatile arterial pressure. Because AAAs display a decrease in elastin concentration and histopathologic changes in which the elastic lamellae are fragmented and degraded, the loss of elastin and its biophysical properties has been considered an essential feature (Campa, et al., Artherosclerosis, 1987, 65:13-21; White et al., J. Vasc. Surg., 1993, 17:371-381; Halloran, et al., J. Surg. Res., 1995, 8:85-92). The fact that most aneurysms arise in the infrarenal aorta has been attributed to the fact that aortic elastin content and the number of elastic lamellae are both normally lower in this region than in more proximal parts of the aorta. The infrarenal aorta would therefore appear to be predisposed to aneurysms induced by any process causing accelerated elastin degradation.
Lysyl oxidase (LO, E.C. 1.4.3.13) initiates covalent crosslinking between and within the molecular units of elastin and of collagen by oxidizing peptidyl lysine in these proteins to peptidyl α-aminoadipic-δ-semialdehyde. The peptidyl aldehyde can then condense with neighboring amino groups or peptidyl aldehydes to form the covalent crosslinkages found in fibrillar collagen and elastin (Kagan, Biology of the Extracellular Matrix, 1986, 321-398). LO contains one mole tightly bound copper (II) cofactor per mole of purified, 32 kDa enzyme which correlates with the maximum expression of enzyme activity. The copper cofactor is bound in a tetragonally distorted, octahedrally coordinated ligand field (Gacheru et al., J. Biol. Chem., 1990, 265:19022-19027). A full length cDNA predicted to encode a protein of 409 amino acids (46 kDa) was first identified within a neonatal rat aorta cDNA λgt11 expression library using anti-bovine lysyl oxidase antiserum. Human (Hamalainen et al., Genomics, 1991, 17:544-548; Mariani et al., Matrix, 1992, 12:242-248), chick (Wu et al., J. Biol. Chem., 1992, 267:24199-24206) and mouse (Kenyon et al., Science, 1991, 253:802) LO cDNAs have now been cloned and sequenced, revealing the presence of both conserved and divergent sequence elements among the four predicted LO protein sequences.
A human cDNA species encoding a predicted lysyl oxidase-like (LOL) protein has been cloned and mapped to chromosome 15q24-q25. The homology of this LOL gene to LO begins at the exon 1-2 boundary in the mouse LO gene (Kenyon et al., J. Biol. Chem., 1993, 268:18435-18437). More recently, a novel cDNA with a predicted protein sequence is 48% homologous to LO and LOL has been identified in senescent human fibroblasts (Saito et al., J. Biol. Chem., 1997, 272:8157-5160). The existence of this series of highly related genes implies the existence of a lysyl oxidase gene family, additional members of which may yet be identified. However, the nature and catalytic function of the expressed protein product of these genes has been documented only for that coding for the known lysyl oxidase enzyme species of connective tissues. Recent studies indicate that LO activity may be modulated by estrogen receptors (Ozasa et al., Endocrinology, 1981, 109:618-621; Sanada et al., Biochim. Biophys. Acta., 1978, 541:408-413).